A 6-year-old boy presents with intense pruritus and thickened skin with accentuated skin markings in the antecubital and popliteal fossae. His mother reports a 3-year history of dry skin and recurrent flares triggered by soaps and stress. On examination, you note infraorbital creases and lateral eyebrow thinning. The structure marked **A** in the diagram shows the characteristic flexural lichenification pattern. Which of the following genetic mutations is most commonly associated with the pathogenesis of this condition?

Explanation

## Why Loss-of-function mutation in the filaggrin gene (FLG) on chromosome 1q21 is right The clinical presentation described—childhood flexural lichenification, xerosis, intense pruritus, and the stigmata of Dennie-Morgan folds and Hertoghe sign—is classic for atopic dermatitis (AD). The SME anchor explicitly states that filaggrin (FLG) loss-of-function mutations on chromosome 1q21 occur in up to 50% of moderate-to-severe AD cases and represent the "genetic skin barrier dysfunction" component of the two-hit model. Filaggrin is a key structural protein of the stratum corneum; its loss reduces natural moisturizing factor, raises skin pH, and allows transepidermal water loss and allergen penetration—the fundamental barrier defect in AD. This is the most common and well-established genetic cause of AD pathogenesis (Bolognia Dermatology 5e Ch 12; Harrison 21e Ch 56). ## Why each distractor is wrong - **Gain-of-function mutation in the IL-4 receptor gene**: IL-4 and IL-13 dysregulation are part of the Th2-skewed immune response (the second hit), not the primary genetic barrier defect. Gain-of-function mutations in IL-4R are rare and not the hallmark genetic finding in AD. - **Loss-of-function mutation in the claudin-1 gene on chromosome 16**: While claudin-1 mutations cause neonatal ichthyosis with sclerosing cholangitis (NISCH), a rare monogenic disorder, they are NOT the most common genetic cause of AD. Filaggrin mutations are far more prevalent in AD populations. - **Missense mutation in the SPINK5 gene encoding LEKTI protease inhibitor**: SPINK5 mutations cause Netherton syndrome, a distinct genodermatosis with ichthyosis linearis circumflexa and atopy-like features, but this is not the primary genetic basis of common AD. **High-Yield:** Filaggrin (FLG) loss-of-function mutations on chromosome 1q21 are found in up to 50% of moderate-severe AD and represent the "genetic hit" in the two-hit model of AD pathogenesis; barrier dysfunction precedes immune dysregulation. [cite: Bolognia Dermatology 5e Ch 12; Harrison 21e Ch 56]